The specific aims of this competitive renewal application are: (1) Completion of a total synthesis of kijanolide. (2) Completion of a total synthesis of superstolide A. (3) Development of an efficient and highly stereoselective total synthesis of eleutherobin. (4) Completion of the stereostructure assignment and total synthesis of quartomicins A3 and D3. (5) Exploration of the scope of the acyclic (z)-diene Diels- Alder reaction. (6) Completion of a total synthesis of the lepidicin aglycone. The targets for these investigations possess a range of interesting and significant biological properties. Kijanolide is the aglycone of kijanimicin that is active against an unusual range of microorganisms, including Plasmodium burgher and P. chabaudin (e.g., malaria); superstolide A exhibits potent cytotoxicity (IC50 10-100nM) against several cancer cell lines such as murine P388 leukemia cells, human nasopharyngeal cells, and non-small-cell lung carcinoma cells; eleutherobin exhibits extremely significant potency (IC50 10-15 nM) toward selected breast, renal, ovarian, and lung cancer cell lines, similar to those observed for paclitaxel (taxol), and competes with taxol for the taxol binding site on the microtubule polymer; the quartromicins exhibit excellent antiviral activity against herpes simplex virus type 1, influenza virus type A, and human immunodeficiency virus. The central theme of this proposal is the development of highly stereoselective syntheses of biologically active natural products by routes involving Diels-Alder reactions. While in the preceding grant periods the primary focus was on the development use of intramolecular Diels-Alder reactions in the synthesis of complex natural products, the methodological focus of the present proposal is significantly broadened by the proposed investigations of the acyclic (Z)-diene Diels-Alder reaction which promises to significantly expand the scope of Diels-Alder reactions in organic synthesis.